The present invention relates to the field of material science and, more particularly, to novel composite structures which can be used for delivering therapeutic agents.
Organ and tissue failure or loss is one of the most frequent and devastating problems still challenging human health care. Tissue regeneration is a new discipline where living cells, being, for example, autologous, allogenic, or xenogenic cells, are used to replace cells lost as a result of injury, disease or birth defect in a living subject.
Tissue regeneration typically involves the preparation of delicate polymeric structures that serve as biodegradable scaffolds incorporating bioactive molecules and/or cells. Such biodegradable scaffolds are often further utilized for in vitro studies of tissues, cells, bioactive agents and the interactions therebetween.
An efficient scaffold for tissue regeneration is typically made of biodegradable structural elements, preferably fibers, in which biologically active molecules can be incorporated and be controllably released over time.
Fibrillar biodegradable scaffolds are ideal particularly when thin, delicate structures are needed, for example in nerve regeneration applications. They can also be used to build implants and other medical devices that combine drug release with other functions, such as mechanical support for a regenerating tissue or as stents.
Polymeric scaffolds that are presently used in tissue regeneration and other applications are preferably biodegradable, meaning that over time the polymer breaks down chemically, metabolically (by biological processes such as hydrolysis or enzymatic digestion) and/or mechanically.
Biodegradable structural elements, such as fibers, have been known and used for many years in many applications such as, for example, fishing materials, for example, fishing lines and fish nets; agricultural materials, for example, insect or bird nets and vegetation nets; cloth fibers and non-woven fibers for articles for everyday life, for example, disposable women's sanitary items, masks, wet tissues (wipes), underwear, towels, handkerchiefs, kitchen towels and diapers; and medical supplies, for example, operating sutures which are not removed, operating nets and suture-reinforcing materials. The biodegradability of these elements renders them highly suitable for constructing medical devices as well as environmental-friendly products. Ample description of biodegradable fibers can be found, for example, in U.S. Pat. Nos. 6,045,908, 6,420,027, 6,441,267, 6,645,622 and 6,596,296.
Biodegradable fibers are typically produced by conventional methods such as, for example, solution spinning, electro-spinning and/or melt-spinning techniques. These fibers are typically made from a single polymer or a co-polymer or from a blend of polymers such as, for example, poly(glycolic acid), poly(L-lactic acid), poly(DL-lactic acid), poly(glycolic-co-lactic acid), poly(3-hydroxybutyric acid), polycaprolactone, polyanhydride, chitin, chitosan, sulfonated chitosan, various natural and derivatized polysaccharide polymers, natural polymers or polypeptides such as reconstituted collagen or spider silk, as well as other various aliphatic polyesters consisting of a dibasic acid and a diol.
Since non-toxicity is an inherent prerequisite for biodegradable polymers that are designed for clinical applications, the starting materials, the final product and the optional break-down products must be non-toxic and benign. Thus, for example, degradation of a biodegradable polyester, such as poly(lactic acid) or poly(glycolic acid), involves a hydrolytic cleavage which results in carbon dioxide and water as non-toxic and benign end products.
The total degradation time of biodegradable polymers can vary from several days to several years, depending mainly on the chemical structure of the polymer chains, and physical properties such density, surface area and size of the polymer. During the degradation process a controllable release of biological agents that are attached thereon and/or encapsulated therein can be effected. Table A below presents the typical degradation time required for complete loss of mass (in time units of months) of some commonly used biodegradable polymers.
TABLE ADegradation time to completemass loss. Rate also depends onPolymerpart geometry (months)PGA 6 to 12PLLA>24PDLLA12 to 16PCL>24PDO 6 to 12PGA-TMC 6 to 1285/15 PDLGA5 to 675/25 PDLGA4 to 565/35 PDLGA3 to 450/50 PDLGA1 to 2PGA abbreviates polyglycolide;PLLA abbreviates poly(l-lactide);PDLLA abbreviates poly(dl-lactide);PDO abbreviates poly(dioxanone);PGA-TMC abbreviates poly(glycolide-co-trimethylene carbonate); andPDLGA abbreviates poly(dl-lactide-co-glycolide).
When used in clinical applications, the biodegradable polymer composing a scaffold is selected according to its properties. Thus, for example, semi-crystalline polymers such as poly(L-lactic acid) (PLLA) can be used in implants that require good mechanical properties such as sutures, devices for orthopedic and cardiovascular surgery, and stents. Amorphous polymers, on the other hand, such as poly(DL-lactic-co glycolic acid) (PDLGA), are attractive in drug release applications, where it is important to have homogenous dispersion of the active species within the monophasic matrix. The degradation rate of these polymers is determined by the initial molecular weight, the exposed surface area, the polymer's degree of crystallinity and (in the case of co-polymers) quantitative ratio of the two co-monomers.
Presently known fibrillar scaffolds for, for example, tissue regeneration are composed of biodegradable fibers that build bulky, “spaghetti-like” structures, whereby biologically active agents are trapped in the voids between adjacent fibers. Typically the scaffold is first prepared and then the biologically active agents are introduced. Since the bioactive agents are not incorporated into the biodegradable fibers but are practically soaked into the fiber-made scaffold, these drug delivery forms display relatively uncontrolled drug release profiles, a feature that is oftentimes antithetical to the goal of drug delivery.
The currently followed paradigm which provides partial solution to the abovementioned limitations is the use of drug-loaded fibers, wherein the bioactive agent is incorporated into the fibers which are used as basic building-blocks of drug-delivering scaffolds and vehicles.
The present main obstacle to successful incorporation in and delivery from biodegradable structures and scaffolds is the inactivation of bioactive molecules by the exposure to high temperatures or harsh chemical environments during the production of the drug-loaded fibers [Thomson, R. C., et al., “Polymer scaffold processing”, in: Lanza R P, Langer R, Vacanti J, editors. Principles of Tissue Engineering, New York: Academic Press; 2000. pp. 251-262].
Nevertheless, few controlled-release fiber systems based on biodegradable polymers and incorporating bioactive molecules have been investigated to date. The two basic types of such drug-loaded fibers are monolithic fibers and reservoir fibers.
In systems that use monolithic fibers the drug is dissolved or dispersed throughout the polymer fiber. For example, organic (hydrophobic) drugs such as curcumin, paclitaxel and dexamethasone have been melt spun with poly(L-lactic acid) (PLLA) to generate drug-loaded fibers [Su, S. H., et al., Circulation, 2001, 104:11, pp. 500-507] and water-soluble (hydrophilic) drugs have been solution spun with PLLA [Alikacem, N., et al., Invest. Ophthalmol. Vis. Sci., 2000, 41, pp. 1561-1569]. Various steroid-loaded fiber systems have demonstrated the expected first order release kinetics [Dunn, R. L., et al., “Fibrous polymer for the delivery of contraceptive steroids to the female reproductive track”, in Lewis DH, editor, “Controlled Release of Pesticides and Pharmaceuticals”, New York: Plenum Press, 1981, p. 125-146]. A recently published work have demonstrated the encapsulation of a limited amount of partially active (after release) human β-nerve growth factor (NGF), which was stabilized by a carrier protein, bovine serum albumin (BSA), in a copolymer of ε-caprolactone and ethyl ethylene phosphate (PCLEEP) produced by electro-spinning [Sing, Y. C. et al., Biomacromolecules, 2005, 6 (4), pp. 2017-2024].
U.S. Pat. Nos. 6,485,737, 6,596,296 and 6,858,222, U.S. Patent Application having the Publication No. 20050106211 and WO 01/10421 teach the fabrication and use of drug-releasing biodegradable monolithic fibers. The fibers are made by mixing the bioactive agent in a polymeric solution which in turn is converted into fibers by extruding the mixture into a coagulating bath. These fibers are ultimately limited in the mechanical properties as compared to fibers which are made of similar polymers without the bioactive agent, and limited in the type of bioactive agents which can undergo and survive this particular production process.
The use of monolithic fibers in drug delivery systems thus suffers several drawbacks including, for example, a limited control of the drug-release profile, and the incorporation of a foreign, non-polymeric substance and/or the formation of pores in the core structure, which adversely affect the strength and/or flexibility of the fibers and in some cases weaken the infrastructure of the fibers.
In systems that use hollow reservoir fibers, drugs such as dexamethasone and methotrexane are located in a hollowed, internal section of the fiber [Eenink, M. D. J., et al., J. Control. Rel., 1987, 6, pp. 225-237; Polacco, G., et al., Polymer International, 2002, 51(12), pp. 1464-1472; and Lazzeri, L., et al., Polymer International, 2005, 54, pp. 101-107]. These systems also suffer disadvantages such as a limited control of the drug-release profile, a weakened infrastructure of the fibers and complicated production procedure.
Hence, although the use of fibers in various medical applications such as tissue regeneration is a promising discipline, the presently known methods for producing such fibers which can incorporate and deliver bioactive agents are limited by poor mechanical properties of the resulting fiber and/or poor drug loading and/or uncontrollable drug release. Furthermore, many bioactive agents (for example, proteins) do not tolerate melt processing, organic solvents and other conditions which are typical for polymeric fiber production.
There is thus a widely recognized need for, and it would be highly advantageous to have biodegradable composite structures, preferably fibrous structures, which can be loaded with and controllably-release bioactive agents, while maintaining the desired mechanical properties of the structure and retaining the activity of the bioactive agents, and which are devoid of the above limitations.